Synthesis, biochemical evaluation and structural studies of novel antiproliferative βeta-lactams
Citation:
Niamh O'Boyle, 'Synthesis, biochemical evaluation and structural studies of novel antiproliferative βeta-lactams', [thesis], Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical Sciences, 2010, pp 499Download Item:
Abstract:
The synthesis and antiproliferative evaluation of anti-cancer β-lactams targeting tubulin, heat shock protein 90 and the estrogen receptor is described. Compounds were planned to include relevant substituents known to confer target selectivity and included a diverse range in order to discern meaningful structure-activity relationships. The core β-lactam heterocycle was formed using established chemistry - the Staudinger and Reformatsky reactions. The Staudinger reaction was employed for the majority of analogues as the necessary synthetic precursors were readily available. All products were fully characterised. A library of over 100 combretastatin A-4 analogues containing the β-lactam core scaffold were prepared and evaluated for antiproliferative activity. Phenolic compound 181 was particularly potent, with activity in the picomolar range for a variety of cell types. Combretastatin A-4 is a known tubulin-targeting agent that binds at the colchicine-binding site, and selected β-lactam analogues including 181 inhibited the polymerisation of tubulin at low micromolar concentrations.
Author: O'Boyle, Niamh
Advisor:
Meegan, Mary JaneQualification name:
Doctor of Philosophy (Ph.D.)Publisher:
Trinity College (Dublin, Ireland). School of Pharmacy & Pharmaceutical SciencesNote:
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